DESCRIPTION (Applicant?s Abstract): Although the molecular signals that regulate epileptogenesis remain largely unknown, recent progress in the neurotrophic factor field has generated an exciting hypothesis, that brain-derived neurotrophic factor (BDNF), a member of the NGF family of neurotrophins, plays a causal role in the development of epilepsy. As structural plasticity is a striking feature of partial epileptogenesis in humans and animal models, the goal of this research proposal is to use molecular biological, brain slice, and neuroanatomical methods to test the hypothesis that inappropriate levels and/or sites of BDNF action in hippocampus, as a consequence of epileptiform activity, contribute to epileptogenesis by altering neuronal morphology to generate progressive hyperexcitability. The experimental focus will be on the regulation of dentate granule cell morphology by BDNF and other neurotrophins in the normal and epileptic hippocampus as striking and specific morphological changes in these neurons are identified with limbic epilepsy. The three specific aims are: 1) to determine if elevated levels of BDNF in hippocampus induce changes in dentate granule neuron morphology that are associated with epileptogenesis; 2) to determine the roles of endogenous neurotrophins in regulating morphology of dentate granule neurons; and 3) to relate neurotrophin regulation of dentate granule cell morphology to epileptogenesis. Identification and understanding of signaling molecules such as BDNF that may contribute to epileptogenesis are vital both to understanding its underlying the cellular mechanisms as well as to the rational development of new avenues of anti-epileptogenic therapies.